Dataset Information

Histological hallmarks and role of Slug/PIP axis in pulmonary hypertension secondary to pulmonary fibrosis.

ABSTRACT: Pulmonary hypertension secondary to pulmonary fibrosis (PF-PH) is one of the most common causes of PH, and there is no approved therapy. The molecular signature of PF-PH and underlying mechanism of why pulmonary hypertension (PH) develops in PF patients remains understudied and poorly understood. We observed significantly increased vascular wall thickness in both fibrotic and non-fibrotic areas of PF-PH patient lungs compared to PF patients. The increased vascular wall thickness in PF-PH patients is concomitant with a significantly increased expression of the transcription factor Slug within the macrophages and its target prolactin-induced protein (PIP), an extracellular matrix protein that induces pulmonary arterial smooth muscle cell proliferation. We developed a novel translational rat model of combined PF-PH that is reproducible and shares similar histological features (fibrosis, pulmonary vascular remodeling) and molecular features (Slug and PIP upregulation) with human PF-PH. We found Slug inhibition decreases PH severity in our animal model of PF-PH. Our study highlights the role of Slug/PIP axis in PF-PH.

SUBMITTER: Ruffenach G

PROVIDER: S-EPMC6728601 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Histological hallmarks and role of Slug/PIP axis in pulmonary hypertension secondary to pulmonary fibrosis.

Ruffenach Gregoire G Umar Soban S Vaillancourt Mylene M Hong Jason J Cao Nancy N Sarji Shervin S Moazeni Shayan S Cunningham Christine M CM Ardehali Abbas A Reddy Srinivasa T ST Saggar Rajan R Fishbein Gregory G Eghbali Mansoureh M

EMBO molecular medicine 20190829 9

Pulmonary hypertension secondary to pulmonary fibrosis (PF-PH) is one of the most common causes of PH, and there is no approved therapy. The molecular signature of PF-PH and underlying mechanism of why pulmonary hypertension (PH) develops in PF patients remains understudied and poorly understood. We observed significantly increased vascular wall thickness in both fibrotic and non-fibrotic areas of PF-PH patient lungs compared to PF patients. The increased vascular wall thickness in PF-PH patient ...[more]

PMID: 31468711

Similar Datasets

Project description:RationaleAn activated vasoconstrictive, proliferative, and fibrotic axis of the renin angiotensin system (angiotensin-converting enzyme [ACE]/angiotensin [Ang]II/AngII type 1 receptor) has been implicated in the pathophysiology of pulmonary fibrosis (PF) and pulmonary hypertension (PH). The recent discovery of a counterregulatory axis of the renin angiotensin system composed of ACE2/Ang-(1-7)/Mas has led us to examine the role of this vasoprotective axis on such disorders.ObjectivesWe hypothesized that Ang-(1-7) treatment would exert protective effects against PF and PH.MethodsLentiviral packaged Ang-(1-7) fusion gene or ACE2 cDNA was intratracheally administered into the lungs of male Sprague Dawley rats. Two weeks after gene transfer, animals received bleomycin (2.5 mg/kg). In a subsequent study, animals were administered monocrotaline (MCT, 50 mg/kg).Measurements and main resultsIn the PF study, bleomycin administration resulted in a significant increase in right ventricular systolic pressure, which was associated with the development of right ventricular hypertrophy. The lungs of these animals also exhibited excessive collagen deposition, decreased expression of ACE and ACE2, increased mRNA levels for transforming growth factor β and other proinflammatory cytokines, and increased protein levels of the AT₁R. Overexpression of Ang-(1-7) significantly prevented all the above-mentioned pathophysiological conditions. Similar protective effects were also obtained with ACE2 overexpression. In the PH study, rats injected with MCT developed elevated right ventricular systolic pressure, right ventricular hypertrophy, right ventricular fibrosis, and pulmonary vascular remodeling, all of which were attenuated by Ang-(1-7) overexpression. Blockade of the Mas receptor abolished the beneficial effects of Ang-(1-7) against MCT-induced PH.ConclusionsOur observations demonstrate a cardiopulmonary protective role for the ACE2/Ang-(1-7)/Mas axis in the treatment of lung disorders.

Dataset Information

Histological hallmarks and role of Slug/PIP axis in pulmonary hypertension secondary to pulmonary fibrosis.

Publications

Histological hallmarks and role of Slug/PIP axis in pulmonary hypertension secondary to pulmonary fibrosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets